CoChat
Sign Up
Cited by 299Barrier Structure and Function StudiesNanoparticle-Based Drug DeliveryDiffusion Coefficients in Liquids

Diffusion of Macromolecules in the Brain: Implications for Drug Delivery

Open access
Wolak, Daniel J., Thorne, Robert G.·2013·Molecular Pharmaceutics
DOI 10.1021/mp300495ePMC PMC3646902
Open this paper in CoChat — free account

Abstract

Therapeutics must diffuse through the brain extracellular space (ECS) in order to distribute within the central nervous system (CNS) compartment; this requirement holds both for drugs that are directly placed within the CNS (i.e., central input) and for drugs that cross the barriers separating blood and brain following systemic administration. The diffusion of any substance within the CNS may be affected by a number of properties associated with the brain microenvironment, e.g., the volume fraction, geometry, width, and local viscosity of the ECS, as well as interactions with cell surfaces, the extracellular matrix, and components of the interstitial fluid. Here, we discuss ECS properties important in governing the distribution of macromolecules (e.g., antibodies and other protein therapeutics), nanoparticles and viral vectors within the CNS. We also provide an introduction to some of the methods commonly applied to measure diffusion of molecules in the brain ECS, with a particular emphasis on those used for determining the diffusion properties of macromolecules. Finally, we discuss how quantitative diffusion measurements can be used to better understand and potentially even improve upon CNS drug delivery by modeling delivery within and across species, screening drugs and drug conjugates, evaluating methods for altering drug distribution, and appreciating important changes in drug distribution that may occur with CNS disease or injury.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1021/mp300495e

Cites

98 of 98 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The intrinsic hydraulic permeability of the human perivascular space is far greater than the width of the cortical extracellular space.

    “others have reported that the intrinsic hydraulic permeability of the human perivascular space is far greater than the width of the cortical extracellular space (1).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [1]

    In “Important Brain Extracellular Space Parameters,” the paper says perivascular spaces may have much higher intrinsic hydraulic permeability than the neuropil’s extracellular space. It compares permeability with permeability, not permeability with width; its width comparison uses perivascular measurements from rodents and humans but extracellular-space measurements from rats, so it does not establish the claim specifically for humans. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is well supported by animal studies with a similar experimental setup.

    “Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is, however, well supported by animal studies with a similar experimental setup to ours (1, 47-49).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [1]

    In “Important Brain Extracellular Space Parameters” (page not provided), the review cites experimental observations of transport in perivascular spaces and says these spaces may allow flow into and out of brain parenchyma. It does not establish widespread penetration specifically from CSF along arterial spaces, or show that the animal studies used a setup similar to the citing authors’ study. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Further distribution of gadobutrol within the brain cortex interstitial compartment should be expected to be predominantly driven by diffusive flux.

    “further distribution within the brain cortex interstitial compartment should accordingly be expected to be predominantly driven by diffusive flux (1).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [1]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. [11]Paxinos G Mai JK The Human Nervous System Elsevier Amsterdam 2004
  2. [31]Briscoe J Lawrence PA Vincent JP Generation and Interpretation of Morphogen Gradients Cold Spring Harbor Laboratory Press Cold Spring Harbor, NY 2010 308
  3. [51]Weiss TF Cellular biophysics MIT Press Cambridge, Mass 1996
  4. [52]Berg HC Random Walks in Biology Princeton University Press Princeton, NJ 1993

Cited by

Sorted by citations

Related

Authors
Wolak, D. J., & Thorne, R. G.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Thorne, Robert G.
ORCID
Venue
Molecular Pharmaceutics
Publisher
American Chemical Society (ACS)
Published
2013-01-31
Volume
10
Issue
5
Pages
1492-1504
ISSN
  • 1543-8384 (ISSN-L)
  • 1543-8392
DOI
10.1021/mp300495e
PMC
PMC3646902
OpenAlex
W2040880670
Cited by
299
References
98
Citations by year
2026: 17 · 2025: 21 · 2024: 16 · 2023: 26 · 2022: 35 · 2021: 19 · 2020: 26 · 2019: 32 · 2018: 18 · 2017: 25 · 2016: 23 · 2015: 16 · 2014: 19 · 2013: 6
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • Molecular Pharmaceutics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Wisconsin-Madison
  • National Institutes of Health (KL2TR000428, UL1TR000427)
  • U.S. Public Health Service (T32 EBO11424)
  • National Institute of Biomedical Imaging and Bioengineering (T32EB011434)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Physical Sciences › Chemistry › Spectroscopy › Diffusion Coefficients in Liquids
Keywords
macromolecular diffusion, brain extracellular space, brain drug delivery, central nervous system, extracellular matrix, interstitial fluid, blood-brain barrier, nanoparticles, viral vectors, immunoglobulins, therapeutic proteins, diffusion measurement methods, central nervous system disorders, central nervous system injury
MeSH terms
Animals, Biological Transport, Blood-Brain Barrier, Brain, Central Nervous System Diseases, Extracellular Space, Humans, Models, Neurological, Drug Delivery Systems, Macromolecular Substances

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review